Primary and metastatic brain tumors occur more commonly in males than females. This is true regardless of age or region of the world. Thus, sex must affect fundamental mechanisms of neoplastic growth in the central nervous system. In preliminary studies we established conditions that result in the transformation of male but not female astrocytes. This experimental paradigm is an unprecedented opportunity to define the molecular basis for the effects of sex on tumorigenesis. We found that sex affects global gene expression, activation of the tumor suppressor p21cip1, induction of a stem cell phenotype, growth kinetics, cellular senescence and patterns of intracranial malignant growth. Moreover, we found sex differences in human GBM stem cells. In this proposal we will exploit these murine and human GBM models to define the molecular basis for the effect of sex on brain tumorigenesis.
In Specific Aim 1 we build on preliminary findings that sexually dimorphic expression of the growth inhibitory molecule p202 results in differential induction of the tumor suppressor p21cip1 and thereby blocks transformation in female astrocytes.
In Specific Aim 2 we will follow up on preliminary studies that indicate stem cells are more easily induced in male astrocytes and define how sex, multiple initiating oncogenic events, X chromosome reactivation and cell of origin interact to regulate transformation.
In Specific Aim 3 we perform validation studies with human male and female GBM stem cell cultures and test the hypothesis that sex differences in GBM stem cells will impact on responses to therapeutic targeting of CXCR4. Together these studies will advance of fundamental knowledge of cancer biology and have the potential to impact on our approach to treating patients with malignant brain tumors.

Public Health Relevance

Successful cancer therapy may require tailoring treatment approaches to the individual and their unique cancer. We determined that sex exerts a profound effect on early events during the genesis of malignant brain tumors. These findings have significant implications for both basic cancer biology and clinical neuro-oncology. The aim of this proposal is to define the molecular mechanisms by which sex affects brain tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA174737-01A1
Application #
8691173
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Salnikow, Konstantin
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Ostrom, Quinn T; Rubin, Joshua B; Lathia, Justin D et al. (2018) Females have the survival advantage in glioblastoma. Neuro Oncol 20:576-577
Kfoury, Najla; Sun, Tao; Yu, Kwanha et al. (2018) Cooperative p16 and p21 action protects female astrocytes from transformation. Acta Neuropathol Commun 6:12
Ippolito, Joseph E; Yim, Aldrin Kay-Yuen; Luo, Jingqin et al. (2017) Sexual dimorphism in glioma glycolysis underlies sex differences in survival. JCI Insight 2:
Warrington, Nicole M; Sun, Tao; Rubin, Joshua B (2015) Targeting brain tumor cAMP: the case for sex-specific therapeutics. Front Pharmacol 6:153
Rubin, Joshua B (2015) Sexual selection and cancer biology. Oncotarget 6:15714-5
Sun, Tao; Plutynski, Anya; Ward, Stacey et al. (2015) An integrative view on sex differences in brain tumors. Cell Mol Life Sci 72:3323-42
Sun, Tao; Warrington, Nicole M; Luo, Jingqin et al. (2014) Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males. J Clin Invest 124:4123-33